Preparation of porous tablets

ABSTRACT

In the production of tablets which are to undergo disintegration in use wherein the tablet components are mixed and pressed into predetermined shape, the improvement which comprises incorporating into the mix at least one inert readily volatilizable solid adjuvant, pressing the mix into shape, and thereafter volatilizing the adjuvant, whereby the resulting tablets are porous, strong, shape retaining and readily disintegratable. Volatilization can be effected by sublimation or application of vacuum. The adjuvant preferably comprises urethane, urea, ammonium carbonate, ammonium bicarbonate, hexamethylene-tetramine, benzoic acid, phthalic anhydride, naphthalene or camphor present in about 5 to 50 percent, especially about 10 to 30 percent, by weight of the total tablet mix.

United States Patent [191 Heinemann et al.

[451 May 20, 1975 PREPARATION OF POROUS TABLETS [75] Inventors: I-IelmutHeinemann, Heidelberg;

Werner Rothe, Hockenheim, both of Germany [73] Assignee: BoehringerMannheim GmbH, Mannheim-Waldhof, Germany [22] Filed: Sept. 10, 1973 [21]Appl. No.: 395,796

[30] Foreign Application Priority Data [58] Field of Search 264/49, 54,117, 140, 101, 264/109, 122; 23/293 R, 293 A; 241/1, 2, 18, 30; 424/14;239/60; 252/135, 531

[56] References Cited UNITED STATES PATENTS 1,742,515 1/1930 Mandell264/49 X 2,887,437 5/1959 Klioze et a1 424/14 3,175,521 3/1965l-lershberg 424/14 X 3,371,984 3/1968 Kelly et a1 239/60 X 3,424,8421/1969 Numberg 264/117 X 3,632,778 1/1972 Sheth et a1 264/117 X3,639,286 2/1972 Ballestra et a1. 252/135 X 3,649,545 3/1972 Susuki eta1. 252/135 X 3,653,914 4/1972 Schmitt 264/122 X 3,674,700 7/1972 Gaiser252/135 3,719,599 3/1973 Crivellaro et a1. 424/14 X 3,739,048 6/1973Morita 264/54 X 3,781,428 12/1973 l-lennart et a1 239/60 X 3,789,1191/1974 Fusari 264/117 X R18,506 6/1932 Mandel 264/49 X FOREIGN PATENTSOR APPLICATIONS 83,244 12/1971 Germany 264/49 OTHER PUBLICATIONS TheCondensed Chemical Dictionary, Seventh Edition, Completely revised andenlarged by Arthur and Elizabeth Rose, New York, Reinhold, C1966, page995.

Handbook of Chemistry and Physics, 52nd Edition, Editor: Robert C.Weast, Cleveland, Ohio, The Chemical Rubber Co., 01971, Page C-232.

Primary Examiner-Philip E. Anderson Attorney, Agent, or Firm-Burgess &Dinklage & Sprung [5 7] ABSTRACT In the production of tablets which areto undergo disintegration in use wherein the tablet components are mixedand pressed into predetermined shape, the improvement which comprisesincorporating into the mix at least one inert readily volatilizablesolid adjuvant, pressing the mix into shape, and thereafter volatilizingthe adjuvant, whereby the resulting tablets are porous, strong, shaperetaining and readily disintegratable. Volatilization can be effected bysublimation or application of 'vacuum. The adjuvant preferably comprisesurethane, urea, ammonium carbonate, ammonium bicarbonate,hexamethylene-tetramine, benzoic acid, phthalic anhydride, naphthaleneor camphor present in about 5 to 50 percent, especially about 10 to 30percent, by weight of the total tablet mix.

13Claims, No Drawings PREPARATION OF POROUS TABLETS The presentinvention is concerned with a new process for the preparation of poroustablets.

Because of the ease of handling and the simplicity of dosing, not onlypharmaceutical tablets but also reagent tablets are used to an everincreasing extent for diagnostic and analytical purposes. Most activematerials and reagents cannot be tabletted by themselves since they formhard tablets which do not readily break down and, in addition, in manycases, tend to stick in the presses used.

Tablets which break down quickly are only obtained by the addition ofdisintegration agents, such as carboxymethyl-cellulose, starch or thelike; filling materials, such as lactose, phosphates or the like; andlubricants, such as talc, stearic acid, paraffin or the like. Whereas itis simple to find suitable, physiologically compatible adjuvants forpharmaceuticals, reagent tablets which, generally speaking, are to giveoptically clear solutions, cannot be produced or can only be producedwith difficulty in this manner. In particular, the lubricants which aregenerally used and which are intended to prevent the adherence of thetablet masses in the presses used are mostly insoluble in water. It has,therefore, been suggested to press together adhesive reagents with verylarge amounts of readily tablettable fillers or to use very highpressures for the pressing. However, both processes are unsatisfactorysince the tablets formed are either unnecessarily large or are too hardand difficult to break down.

Another known process gives so-called molded tablets." In this case, thetablet components are formed into a paste with water or an organicsolvent, in which at least one of the components partially dissolves, togive a stiff slurry which is formed in special machines to give tablets,whereafter the tablets are carefully dried. Upon evaporation of thesolvent, the substances dissolved therein adhere the undissolvedparticles, whereby the tablets receive their strength; at the same time,small hollow spaces are formed into which solvents can again penetratewhen the tablets are dropped into liquid. Although these tablets aresatisfactory with respect to speed of dissolution they are frequentlytoo soft and brittle due to the presence of very fine canals so thatdifficulties arise in packing and transport. Furthermore, the use of theprocess is limited due to the fact that many reagents, especiallyenzymes and indicators, are damaged by solvents, and organic solventvapors necessitate special safety precautions during the production ofthe tablets.

It is, therefore, an object of the present invention to provide aprocess which permits the production of readily dissolved, poroustablets in conventional tablet presses, without having to addlubricants, explosive agents or solvents.

In accordance with the present invention the conventional process ofmixing tablet components and pressing the mix into predetermined shapeis modified by incorporating into the mix at least one inert readilyvolatilizable solid adjuvant, pressing the mix into shape, andthereafter volatilizing the adjuvant, whereby the resulting tablets areporous, strong, shape retaining and readily disintegratable.

Due to the hard pressing in conventional tabletting machines, there areformed tablets of great mechanical stability and, at the same time, theaddition of sparingly soluble lubricants is unnecessary. Since thepressed tablets, in contradistinction to molded tablets, are

form-stable, they no longer shrink upon removal of the adjuvant.Therefore, when the adjuvant is removed, it

5 leaves behind comparatively large hollow spaces and canals, throughwhich solvent can penetrate.

As adjuvants, there can be used, in principle, all readily sublimablematerials or materials which can readily be converted into gaseousdecomposition products and which are readily tablettable and do notreact with the other components of the tablets. By way of example, theremay be mentioned urethane, urea, ammonium carbonate and bicarbonate,hexamethylenetetramine, benzoic acid, phthalic anhydride, naphthaleneand camphor, urethane being especially preferred.

The tablet masses for water-soluble reagent tablets and pharmaceuticaltablets can, in addition to one or more active materials, containconventional soluble carrier materials, for example sodium chloride,potassium chloride, borax, phosphates, oligosaccharides, polyethyleneglycols, tensides and other appropriate inorganic and organic materials.The volatile solid adjuvants can account for about 5 50 percent andpreferably about -30 percent of the total tablet mass. it beingunderstood that in the case of a high proportion of adjuvant there areformed comparatively large hollow spaces and thus tablets which breakdown more quickly but are also more brittle than in the case of using asmall proportion of adjuvant. Although the adjuvants can be completelyremoved, the production time for the new tablets according to thepresent invention is shortened when the adjuvants are allowed to remainbehind in the tablets in trace amounts, for example of less than about1% by weight.

Where the tablet components are of sufficient ther' mal stability, theadjuvants can be removed by simple heating of the tablets above thesublimation or decomposition point. In the case of sensitive tabletcomponents, for example of enzymes, it is advantageous to work in avacuum, the conventional freeze drying plants with condensationseparator having proved to be especially advantageous for this purpose.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE I Tablet A: 1.850 kg of potassium chloride are sieved andpressed to form tablets of 8 mm diameter containing 185 mg of potassiumchloride.

Tablet Bl: 1.850 kg of potassium chloride are mixed with 350 g ofurethane (ethyl-urethane), sieved and pressed to form tablets of 8 mmdiameter containing 185 mg of potassium chloride and 35 mg of urethane.

The urethane is subsequently sublimed from these tablets over 5 hours ina freeze drying plant at 20C and at a pressure of IO to 10. mm Hg.

Tablet B2: 1.850 kg of potassium chloride are mixed with 350 g ofammonium bicarbonate, sieved and pressed to form tablets of 8 mmdiameter containing 185 mg of potassium chloride and 35 mg of ammoniumbicarbonate.

The ammonium bicarbonate is driven off from these tablets over 8 hoursin a drying cabinet at 90C.

Tablet B3: 1.850 kg of potassium chloride are mixed with 350 g of urea,sieved and pressed to form tablets of 8 mm diameter containing 185 mg ofpotassium chloride and 35 mg of urea.

The urea is sublimed from these tablets over 16 hours in a vacuumcabinet at 110C and 15 mm Hg.

Tablet B4: 1.850 kg of potassium chloride are mixed with 350 g ofurotropin, sieved and pressed to form tablets of 8 mm diametercontaining 185 mg of potassium chloride and 35 mg of urotropin.

The urotropin is removed from these tablets over 16 hours in a vacuumcabinet at 90C and 15 mm Hg.

The results of tests carried out on these tablets are set out in thefollowing Table 1:

TABLE 1 Tablet Height, Hardness. Dissolving Breakability,

mm kg Time, sec. see.

EXAMPLE 2 Tablet C: 1.5 kg of dextrose are granulated with 300 ml of 40percent aqueous alcohol, dried and sieved. The granulate is dry mixedwith 50 g of polyethylene glycol (M.W. 5000 6000) and pressed to formtablets of 8 mm diameter containing 150 mg of dextrose.

Tablet D1: 1.550 kg of dextrose-polyethylene glycol granulate are drymixed with 300 g of urethane. The tablet mass is pressed to form tabletsof 8 mm diameter containing 150 mg of dextrose and 30 mg of urethane.

The urethane is sublimed from these tablets over 8 hours in a dryingcabinet at 40C.

Tablet D2: 1.550 kg of dextrose-polyethylene glycol granulate are drymixed with 300 g of ammonium carbonate. The tablet mass is pressed toform tablets of 8 mm diameter containing 150 mg of dextrose and 30 mg ofammonium carbonate.

The ammonium carbonate is removed from these tablets over 8 hours in adrying cabinet at 75C.

Tablet D3: 1.550 kg of dextrose-polyethylene glycol granulate are drymixed with 300 g of benzoic acid. The tablet mass is pressed to formtablets of 8 mm diameter containing 150 mg of dextrose and 30 mg ofbenzoic acid.

The benzoic acid is sublimed from these tablets over 16 hours in avacuum cabinet at 90C and 15 mm Hg.

Tablet D4: 1.550 kg of dextrose-polyethylene glycol granulate are drymixed with 300 g of camphor. The tablet mass is pressed to form tabletsof 8 mm diameter containing 150 mg of dextrose and 30 mg of camphor.

TABLE 2 Tablet Height, Hardness,

Dissolving Time, sec.

Breakability, sec.

EXAMPLE 3 Tablet E: g of polyethylene glycol (M.W. 5000 6000) aredissolved in 80 ml of 40 percent aqueous ethanol. With this solution,there are mixed 388 g of glucose, which is then dried and sieved. Thegranulate obtained is dry mixed with 12.5 g ofnicotinamide-adenine-dinucleotide (NAD), 3.75 g of2,5-diphenyl-3-(4,5-dimethyl-thiazolyl-2)- tetrazolium bromide (MTT) and0.75 g of N- methylphenazine-methylsulfate (PMS). The mixture is pressedto form tablets of 12 mm diameter, each tablet containing 12.5 mg ofNAD, 3.75 mg of MTT and 0.75 mg of PMS.

Tablet F: 15 g of polyethylene glycol (M.W. 5000 6000) are dissolved in80 ml of 40 percent aqueous alcohol. With this solution, there are mixed388 g of glucose, which is then dried and sieved. The granulate obtainedis dry mixed with 12.5 g of NAD, 3.75 g of MTT, 0.75 g of PMS and 80 gof urethane. The mixture is pressed to form reagent tablets of 12 mmdiameter which contain, per tablet, 12.5 mg of NAD, 3.75 mg of MTT and0.75 mg of PMS. The urethane is sublimed from these tablets over 8 hoursin a freeze drying plant at 0C and 10 to lO 3 mm Hg.

The results of tests carried out on these tablets, in the mannerdescribed in Example 1, are set out in the following Table 3: 45

TABLE 3 Tablct Height,

Hardness, kg

Dissolving Time, sec.

Breakability,

sec.

EXAMPLE 4 Tablet G: 500 g of sodium chloride are ground,

mixed with 116 g of sodium p-nitrophenyl phosphate, precompressed andsieved. There are then pressed tablets of 5 mm diameter each containing1 1.6 mg of sodium p-nitrophenyl phosphate.

Tablet H: 500 g of sodium chloride are ground,

mixed with 116 g of sodium p-nitrophenyl phosphate and 134 g ofurethane, precompressed and sieved. There are then pressed tablets of 5mm diameter containing 11.6 mg of sodium pnitrophenyl phosphate. Thesetablets are heated for 10 hours in a drying cabinet at 30C to sublimethe urethane.

The results of tests carried out on these tablets, in the mannerdescribed in Example 1, are set out in the following Table 4:

The various components of the tablet mix including active materials,adjuvant, carrier, etc., may range in size from about 0,0l to 1,0 andpreferably about 0.05 to 0,5 mm. Desirably the average size of theadjuvant particles ranges from about 5 to 50 percent and preferablyabout to 30 percent of that of the balance of the particles making upthe tablet mix.

It will be appreciated that the instant specification and examples areset -forth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

What is claimed is:

1. In the production of pharmaceutical or reagent tablets which are toundergo disintegration in use wherein the tablet components are mixedand pressed into predetermined shape. the improvement which comprisesincorporating into the mix at least one inert solid adjuvant, sublimableat a temperature up to about 1 10C pressing the mix into tablets, andthereafter subjecting the tablets to at least one of vacuum and heatingto a temperature up to about 1 10C so as to sublime the adjuvant,whereby the resulting tablets are porous, strong, shape retaining andreadily disintegratable.

2. Process according to claim 1, wherein the adjuvant is sublimed byapplication of a vacuum.

3. Process according to claim 1, wherein the adjuvant comprises about 5to 50 percent by weight of the total tablet mix.

4. Process according to claim 3, wherein the adjuvant comprises about 10to 30 percent by weight of the total tablet mix.

5. Process according to claim 1, wherein the tablet mix additionallycomprises a soluble carrier.

6. Process according to claim 1, wherein the adjuvant is urethane.

7. Process according to claim 1, wherein the adjuvant is urea.

8. Process according to claim 1, wherein the adjuvant ishexamethylenetetramine.

9. Process according to claim 1, wherein the adjuvant is benzoic acid.

10. Process according to claim 1, wherein the adjuvant is phthalicanhydride.

11. Process according to claim 1, wherein the adjuvant is naphthalene.

12. Process according to claim 1, wherein the adjuvant is camphor.

13. The product produced by the process of claim 1.

1; 33 UNl'lEl) sm'uss l-A'LENI mutt CERTIFICATE OF CORRECTION Patent No.3 ,885.,O26 4 Dated May 20 1975 Inventor (s) HELMUT HEINEMANN ET AL I Itis certified that error appearsln the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

i 3 "1 Col. 2, line-58, cancel "l0 to l0 and substitute Col. 4, line 2,cancel "l0 to l0 and substitute Col. 4, line'hl, cancel 'l0 to l0 andsubstitute Signed and Sealed this thirtieth Day of September 1975 [SEAL]Arrest:

RUTH ct MASON c. MARSHALL DANN Allesling Officer Commissioner of Palnlsand Trudtmarkx

1. IN THE PRODUCTION OF PHARMACEUTICAL OR REAGENT TABLETS WHICH ARE TOUNDERGO DISINTEGRATION IN USE WHEREIN THE TABLET COMPONENTS ARE MIXEDAND PRESSED INTO PREDETERMINED SHAPE, THE IMPROVEMENT WHICH COMPRISESINCORPORATING INTO THE MIX AT LEAST ONE INERT SOLID ADJUVANT, SUBLIMABLEAT A TEMPERATURE UP TO ABOUT 110*C PRESSING THE MIX INTO TABLETS, ANDTHEREAFTER SUBJECTING THE TABLETS TO AT LEAST ONE OF VACUUM AND HEATINGTO A TEMPERATURE UP TO ABOUT 110*C SO AS TO SUBLIME THE ADJUVANT,WHEREBY THE RESULTING TABLETS ARE POROUS, STRONG, SHAPE RETAINING ANDREADILY DISINTEGRATABLE
 2. Process according to claim 1, wherein theadjuvant is sublimed by application of a vacuum.
 3. Process according toclaim 1, wherein the adjuvant comprises about 5 to 50 percent by weightof the total tablet mix.
 4. Process according to claim 3, wherein theadjuvant comprises about 10 to 30 percent by weight of the total tabletmix.
 5. Process according to claim 1, wherein the tablet mixadditionally comprises a soluble carrier.
 6. Process according to claim1, wherein the adjuvant is urethane.
 7. Process according to claim 1,wherein the adjuvant is urea.
 8. Process according to claim 1, whereinthe adjuvant is hexamethylenetetramine.
 9. Process according to claim 1,wherein the adjuvant is benzoic acid.
 10. Process according to claim 1,wherein the adjuvant is phthalic anhydride.
 11. Process according toclaim 1, wherein the adjuvant is naphthalene.
 12. Process according toclaim 1, wherein the adjuvant is camphor.
 13. The product produced bythe process of claim 1.